Polyglycol ether acid anilides



United States Patent 2,769,838 POLYGLYCOL ETHER ACID ANILIDESApplication November 16, 1954, Serial No. 469,296

Claims priority, application Switzerland November 20, 1953 4 Claims.(Cl. 260562) No Drawing.

This invention relates to poly-1:2-glycol ethers of aliphatica-hYdIOXY-CalbOXYllC acid arylides and particularly to poly-l :Z-glycolethers of the formula in which n represents a whole number greater thanone, R represents hydrogen or a hydrocarbon radical containing at most 7carbon atoms, e. g., methyl, ethyl, propyl, butyl, amyl, hexyl andheptyl radicals, and R and R" each represent a hydrogen atom or a loweralkyl or lower alkoxy-alkyl group, especially a methyl, methoxy methylor ethoxy methyl group, provided that R and R" repre' sent hydrogen inat least n/ 2 of the residues 033-5111- X represents hydrogen or a lowerhydrocarbon radical, such as a lower alkyl radical, e. g. methyl, ethyl,propyl, butyl or amyl radicals, PhenyP represents a phenyl residue,which advantageously contains substituents, for example, one or morealkyl groups, e. g. ethyl, propyl, butyl and especially methyl radicals,free or substituted bydroxyl such as alkoxy groups, e. g. methoxy,ethoxy, propoxy, butoxy or amyloxy radicals, or halogen atoms, and Yrepresents hydrogen or an aromatic residue, advantageously a phenylresidue, or an aliphatic or cycle-aliphatic hydrocarbon radical, such asan alkyl or cyclo-alkyl group containing not more than 7 carbon atoms.

Especially valuable are compounds of the formula in which n represents awhole number from 2 to 20 and preferably from 4 to 8 inclusive, R and Xrepresent hydrogen or a lower alkyl group, especially methyl, ethyl,propyl or butyl, and Y represents hydrogen, a radical having the samemeaning defined for phenyl or an alkyl or cycloalkyl residue containingnot more than 7 carbon atoms, such as methyl, ethyl, butyl cyclopentylor cyclohexyl. Especially valuable are compounds of the last mentionedformula in which phenyl represents a 2:6- dimethyl-phenyl radical, Yrepresents hydrogen or a lower alkyl radical such as a butyl residue,and X represents hydrogen, and R stands for methyl.

The new poly-1:2-glycol ethers possess valuable pharmacologicalproperties. Thus, they exhibit a pronounced anaesthetic action and areuseful as medicaments more particularly as cough depressants. It isnoteworthy that these ether-amides generally exhibit a considerablesolubility in water. Their aqueous solutions possess the characteristicof becoming turbid when heated at a certain temperature which isdependent on the concentration. This temperature in the case of asolution of 10 percent strength is called the turbidity point, and is aphysical constant characteristic of the particular compound. Theturbidity is reversible. Thus upon cooling the solution becomes clearagain.

In generai the poly-1:2-glycol ethers of aliphatic a-hydroxy-carboxylicacid arylides can be prepared by reacting a reactive ester, especiallyan ester of a strong inorganic or organic acid, such as a hydrohalicacid or an organic sulfonic acid, for example, benzene sulfonic acid, ofan aliphatic a-hydroxy-carboxylic acid arylide with a poly-lzZ-glycol,preferably in the form of a metal alcoholate thereof, such as an alkalimetal alcoholate thereof, or in the presence of a condensing agent. Thereaction may be carried out in stages, for example, by first forming inthe manner described above a glycol-(l:2)-ether of an aliphaticoc-hYdl'OXYCHl'bOXYllC acid arylide, which may still contain free glycolhydroxyl groups, or forming a reactive ester thereof, and converting theproduct into a poly- 1:2-glycol ether in the manner described above.

Alternatively a poly-1:2-glycol ether of an aliphatica-hydroxycarboxylic acid halide, especially the chloride is reacted withthe appropriate arylamine, advantageously in the presence of anacid-binding agent, such as an inorganic or organic base, for example, atertiary amine such as pyridine.

Finally an aliphatic a-hydroxy-carboxylic acid arylide may be converteddirectly or in stages into a poly-1:2- glycol ether thereof by treatmentwith an alkylene-1:2 oxide.

The reactions are carried out in the presence or absence of a diluentsuch as an aromatic hydrocarbon, e. 3. benzene or toluene.

The invention also includes the production of mixtures of finalproducts, especially those in which the number n has different meanings,that is to say, an average value. These mixtures can be made inaccordance with the invention, for example, by employing the appropriatepoly- 112-glycol mixtures or hydroxy-derivatives or ethers thereof withthe a-hydroxy-carboxylic acid halides as starting materials, or they canbe formed in the reaction with alkylene-l :2-oxides referred to above.

The new compounds can be used as medicaments in the form ofpharmaceutical preparations which contain them in admixture with apharmaceutical adjuvant as a carrier facilitating the administrationthereof, e. g., a pharmaceutical organic or inorganic carrier materialsuitable for enteral, parenteral or oral application. For the productionof these preparations inert pharmaceutical adjuvants are employed ascarriers, namely, such substances as do not react with the newcompounds, as for example water, gelatinc, lactose, starches, magnesiumstearate, talc, vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, petroleum jelly, cholesterol, or other known medicamentcarriers. The pharmaceutical preparations can be made up, for example,as tablets, dragees, or in liquid form as solutions, suspensions oremulsions, e. g. in the form of elixirs. They are sterilized if desired,and/ or may contain auxiliary substances such as preservative,stabilizing, wetting or emulsifying agents, salts which vary the osmoticpressure or buffer substances. They may also contain othertherapeutically valuable substances.

The following examples illustrate the invention, the parts being byweight unless otherwise stated and the relationship of parts by weightto parts by volume being the same as that of the gram to the cubiccentimeter:

Example 1 The acid chloride (obtained from a solution of 31 parts of theether of penta-ethylene glycol mono-methyl ether with glycollic acid ofthe formula in parts by volume of benzene by heating the solution forone hour at 50 C. with 90 parts by volume of thionyl chloride,distilling oil? the greater part of the thionyl chloride and benzeneunder reduced pressure, removing the last residues of thionyl chlorideby taking up the residue twice in 90 parts by volume of toluene and concentrating in vacuo) is dissolved in 90 parts by volume of toluene, andmixed at C. while stirring, first, dropwise with a solution of 17.7parts of N-butyl-(n)-2:6- dimethyl-aniline in 40 parts by volume oftoluene and then with a solution of 7.9 parts of pyridine in 40 parts byvolume of toluene. After allowing the mixture to stand for 2 hours atroom temperature the greater part of the solvent is evaporated in vacuoand the residue is taken up in 450 parts by volume of chloroform. Thechloroform solution is extracted by agitation three times with 150 partsby volume of 2 N-sulfuric acid, twice with 150 parts by volume of a 1N-solution of caustic soda and with 150 parts by volume of water. Theaqueous layers are then extracted in succession with 200 parts by volumeof chloroform. The combined chloroform layers are finally concentratedby evaporation, and there are obtained therefrom by degassing in a highvacuum as a residue 46.9 parts of ether of penta-ethylene glycolmono-methyl ether with glycollic acid N-butyl-(n)-N-2:6-dirnethylphenylamide of the formula $113 CH(O.OHg.CHI)60.CHg.CO.N

of diethylene glycol mono-methyl ether is run in the C., while stirringinto a s0lu- 250 parts by volume of water on each occasion, and thenevaporated. 220 parts of crude penta-ethylene glycol mono-methyl etherremain behind. By extracting the three aqueous layers five times with500 parts by volume of chloroform on each occasion, there are obtained afurther 250 parts of crude pentaethylene glycol monomethyl ether. Fromthe crude product there is obtained by distillation in a high vacuum of0.01 mm. and at 110 C. 100 parts of a pure ether in the form of acolorless oil.

parts of potassium are then dissolved, while stirring, in 140 parts byweight of penta-ethylene glycol monomethyl ether having a temperature of8090 C. in an atmosphere of hydrogen. The solution is then cooled to 40C., and 12.1 parts of chloracetic acid are added, while stirringstrongly, whereupon a thick milky emulsion is formed and the temperaturerises to 55 C. The mixture is stirred for a further minutes at thattemperature, and then heated at 95 C. for 1 hours. The mixture, whichhas become thinly fluid, is cooled and mixed with 150 parts by volume ofa 1 N-solution of caustic soda. In order to remove the excess ofpentaethylene glycol monomethyl ether, the alkaline solution isextracted once with 1000 parts by volume of chlorowith 50 parts byvolume of a 0.5 N-solution of caustic of parts of regeneratedpenta-ethyleue glycol monomethyl ether. The combined aqueous alkalinelayers are acidified with 35 parts by volume of hydrochloric acid, andthen extracted once with 600 parts by volume of chloroform and 5 timeswith 300 parts by volume of chloroform. From the chloroform solutionthere is obtained by concentration and degassing in a high vacuum at70-80" C. 31.6 parts of the ether of penta-ethylene glycol monomethylether with glycollic acid in the form of a pale brown oil. The crudeether-acid can be purified by way of its methyl ester. The latter isprepared by converting the acid into its acid chlororide by means ofthionyl chlororide, and reacting the acid chloride with methanol. Itdistils as a colorless oil at -147 C. under 0.01 mm. pressure ofmercury, and can easily be rcconverted into the ether-acid by alkalinehydrolysis. in the pure state it is a practically colorless oil solublein water, ethanol and benzene.

The N-butyl-n-Z:6-dimethyl-aniline used in this example is prepared asfollows:

24.2 parts of 2:6-dimethyl-aniline are heated with 27. parts of n-butylbromide in a closed vessel for 14 hours at 100 C. The cooled crystallinemass is recrystallised from parts by volume of water. The crystals,which melt at 214-216 C., are then mixed with a solution of sodiumcarbonate, and the mixture is extracted twice with ether. Afterevaporating the ether, the residue is fractionated in a column, and 30parts of N-butyl- (n)-2:6-dimethyl-aniline distil in the form of acolorless oil at l161l8 C. under 10 mm. pressure of mercury.

Example 2 The acid chloride (obtained from 44.2 parts of the ether ofoctaethylene glycol monomethyl ether with glycollic acid of the formula.

CH3.(O.CH2.CH2)aO.CH2.COOH

by reaction with 100 parts by volume of thionyl chloride in 100 parts byvolume of benzene at 50 0., in a manner analogous to that described inExample is dissolved in 100 parts by volume of toluene and mixed at 0C., While stirring, first dropwise with a solution of 17.7 parts ofN-butyl-(n)-2:6-dimethylaniline in 40 parts by volume of toluene andthen with a solution of 7.9 parts of pyridine in 40 parts by volume oftoluene. The whole is allowed to stand for 3 hours at room temperatureand worked up as described in Example 1. There are obtained 59 parts ofthe other of octa-cthylene glycol monomethyl ether with glycollicacid-N-butyl-(n)-N-2z6-dimethylphenyl-amide of the formulaomtocaromrtocmoo.N 234E} This product is a ethanol, benzene,

converting the latter into its benzene sulfonic acid ester and reactingthe product with diethylene glycol. The mixture is then cooled to 30 C.,and mixed, while stirring with 15.8 parts of chlorosulfonic acid,whereupon the temperature rises to 62 C. After having stirred themixture for a further 1%. hours at 90 C., the product is worked up in amanner analogous to that described in Example 1, and there are obtained,in addition to 192 parts of the regenerated octaethylene glycolmonomethyl ether, 59 parts of the ether of octaethylene glycolmonomethyl ether with glycollic acid in the form of a pale brown powder.This crude ether-acid can also be purified by way of its methyl ester asin the case of the acid described in Example 1. It distils as acolorless oil at 205- 207 C. under 0.01 mm. pressure. The acid caneasily be regenerated from the methyl ester by alkaline hydrolysis andin the pure state the acid is a practically colorless oil soluble inwater, ethanol and benzene.

Example 3 The acid chloride (obtained from 0.5 part of the ether of thepoly-ethylene glycol monomethyl ether with glycollic acid of the formulaCH3.(O.CH2.CH2) .nO-CH2.COOH

in which n has the average value of about 6-8, by heating it in 15 partsby volume of benzene for /2. hour with 15 parts by volume of thionylchloride at 5060 C., and purified as described in Example 1) isdissolved in 5 parts by volume of benzene and mixed at C. with asolution of 4.5 parts of N-butyl-(n)-2:6-dimethylaniline and 1 part ofpyridine in parts by volume of benzene. The mixture is allowed to standat room temperature for 2 hours, and then worked up in a manneranalogous to that described in Example 1. There are obtained 6.2 partsof the ether of polyethylene glycol monomethyl ether with glycollic acidN-butyl-(n)-N-2:6dimethylphenyl-amide of the formula in which n has theaverage value of about 6-8, in the form of a yellow oil which dissolveswell in ethanol, benzene, ethyl acetate and cold water.

For the purpose of purification an aqueous solution of the crude oil of10 percent strength is treated in the warm with a small amount of animalcarbon and filtered. After extraction 3 times with chloroform, theproduct is obtained by evaporation of the chloroform extract as apractically colorless oil.

The new ether-amide is a mixture and as such has a turbidity point of62-63 C. (aqueous solution of 10 percent strength). The ether of thepolyethylene glycol monomethyl ether with glycollic acid (nzabout 6-8)used as starting material in this example is prepared as follows:

5 parts of potassium are dissolved at 100 C. in 140 parts ofpolyethylene glycol monomethyl ether boiling at l-175 C. under 0.005 mm.pressure in an atmosphere of hydrogen. The said ether is obtained byfractional distillations from the commercial poly-ethylene glycolmonomethyl ether having the average molecular weight of 350, and, owingto its boiling range, has an average polymerization number (n) ofapproximately 6-8. The viscous solution is cooled to 35 C., 6 parts ofchloracetic acid are added, whereby the temperature rises to C. Afterstirring the mixture for one hour at 50-60 C. and 2 hours at 100 C., theproduct is worked up in a manner analogous to that described in Example1 for the corresponding ether acid, and there are obtained 24 parts ofthe said glycollic acid-ether in the form of a bright yellow oil, andalso 110 parts of the regenerated polyethylene-glycol monomethyl ether(n=about 6-8) which again boils between and C. under 0.005 mm. pressureof mercury.

The methyl ester of this glycollic acid-ether which can be obtainedeither by way of its acid chloride in a manner analogous to thatdescribed in Example 1 or by reaction of the carboxylic acid with anethereal solution of diazo methane distils as a colorless oil between150 and at 0.005 mm. pressure of mercury.

The free acid can be regenerated therefrom by alkaline hydrolysis in theform of a practically colorless oil, which dissolves well in water,ethanol, benzene and ethyl acetate.

Example 4 The acid chloride (obtained from 4.1 parts of the ether of thepolyethylene glycol monomethyl ether with glycollic acid of the formulaCH3.(O.CH2.CH2) .nO.CH2COOH in which n has the average value of about6-8, by heating it in 15 parts by volume of benzene for one hour with 15parts by volume of thionyl chloride at 50-60 C., and purified asdescribed in Example 1) is dissolved in 5 parts by volume of benzene andmixed at 0 C. with a solution of 3 parts of 2:6-dimethylaniline (boilingat 92-93 C. under 12 mm. pressure) and 0.9 part of pyridine in 10 partsby volume of benzene. After allowing the mixture to stand for one hour,it is taken up in 100 parts by volume of chloroform, agitated with 2 Nhydro-chloric acid, a 1 N-solution of caustic soda and water, and theaqueous layers are extracted with 50 parts by volume of freshchloroform.

The purified chloroform layers yield upon evaporation 5.2 parts of theether of the polyethylene glycol monomethyl ether with glycollicacid-N-Zzo-dimethylphenylamide of the formula in which n has the averagevalue of about 6-8, in the form of a bright yellow oil.

This product dissolves well in water, alcohol, benzene and ethylacetate, and can be decolorized by treating an aqueous solution of 10per-cent strength of the product with animal carbon.

Its turbidity point is 100 solution).

The ether of the polyethylene glycol monomethyl ether with glycolli-cacid used as starting material in this example is prepared as describedin Example 3.

By reacting in an analogous manner the ether from diethylene glycolmonomethyl ether and glycollic acid chloride with 2:6-dimethylanilinethere is likewise obtained in good yield the ether of diethylene glycolmonomethyl ether with glycollic acid-N-ZzG-dimethylphenyl amide of theformula C. (10 percent aqueous CH .(O.CH2.OH O .CHmCOJEIN It has aturbidity point of 50 C. (aqueous solution of 10 percent strength). Theether of diethylene glycol monomethyl ether with glyeollic acid isprepared in the manner described by M. H. Palornaa and T. A. Siitonen,Berichte der Deutschen Chemischen Gesellschaft, vol. 63, page 3120(1930). The corresponding acid chloride is obtained in a manneranalogous to that used for making the first mentioned acid chloride, anddistils at 116-119" C. under 10 mm. pressure of mercury.

Example 5 CH .(O CH .CH O.?Ii.COOH

Calls in which n has the average value of about 6-8, by heating it insolution in 15 parts by volume of benzene for 2 hours with 15 parts byvolume of thionyl chloride at 50-60" C. and purified as described inExample 1 is dissolved in 10 parts by volume of toluene, and mixed at C.in succession with a solution of parts of 2:6-dimethylaniline in 5 partsby volume of toluene and with a solution of 1.1 parts of pyridine in 5parts by volume of toluene. After allowing the mixture to stand for 2hours, the mixture is taken up in 100 parts by volume of chloroform,agitated with 2 N-hydrochloric acid, a 2 N-solution of caustic soda andwater and the aqueous layers are extracted with 50 parts chloroform. Byevaporating the combined chloroform layers there are obtained 6 parts ofthe ether of the polyethylene glycol monomethyl ether witha-hydroxycaproic acid of the formula in which n has the average value ofabout 68, and which, after treatment with animal carbon in the form ofan aqueous solution of percent strength, is a colorless oil whichdissolves well in cold water, ethanol, benzene and ethyl acetate.

Its turbidity point is 3536 C. (aqueous solution of 10 percentstrength).

The carboxylic acid mixture used as starting material in this example isprepared as 'follows:

4.4 parts of potassium are dissolved at 90 atmosphere of hydrogen, whilestirring in 90 parts of polyethylene glycol monomethyl ether having aboiling range of 135-175 C. under 0.005 mm. pressure of mercury(-n=about 6-8), whereby the temperature rises to C. in an 110 C. Aftercooling the mixture to 25 C., 10 parts v of e-bromocaproic acid areadded, and the whole is stirred for a further 3 hours while thetemperature is slowly raised to 100 C. The product is worked up in themanner analogous to that described in Example I for the correspondingether-acid, and there are obtained 12.6 parts of the ether ofpolyethylene glycol monomethyl ether with a-hydroxycaproic acid in theform of a yellow oil.

Example 6 The acid chloride, obtained from 6 parts of the ether i ofheptaethylene glycol monomethyl ether with glycollic acid of the formulaCH3. (O.CH2.CH2).7O.CH2.COOH

by reaction with 25 parts of thionyl chloride in 20 parts by volume ofbenzene in a manner analogous to that described in Example 1 isdissolved in parts by volume of toluene and mixed at 0 C. in successionwith a solution of 6 parts of paraethoxy-aniline in 10 parts by volumeof toluene and a solution of 1.2 parts of pyridine in 5 parts by volumeof toluene. After allowing the mix ture to stand at room temperature for2 hours it is taken up in 100 parts by volume of chloroform, shaken with2 N-hydrochloric acid, a 2 N solution of caustic soda and water, and theaqueous layers are extracted with 50 parts by volume of freshchloroform.

The residue obtained from the chloroform solution by evaporation isdissolved in 100 parts by volume of water and treated with animalcarbon. After repeated extraction with chloroform, of the filtered andpractically by volume of fresh colorless aqueous solution there areobtained 7.4 parts of the ether of hepta-ethylene glycol-monomethylether with glycollic acid N-para-ethoxyphenylamide of the formula in theform of a pale yellow oil which dissolves well in cold water, ethanoland benzene.

Its turbidity point is 71 C. (aqueous solution of 10 percent strength).

The carboxylic acid used in this example as starting material isprepared as follows:

50 parts of pentaethylene glycol monomethyl ether are dissolved in 100parts by volume of benzene, and mixed tirc-pwise with 35 parts by volumeof benzene sulfochloride, while stirring and cooling for /2 hour at -30C. At the same time 15 parts of pulverized sodium chloride areintroduced in uniform portions. The whole is stirred for a further 2 /2hours, and is then allowed to stand overnight without stirring. Themixture is then filtered with suction to remove precipitated salts, andthe filtrate is shaken with 20 parts by volume of an aqueous solution ofammonia of percent strength for 4 hours. The benzcne sulfochloride whichmay still be present is converted into the alkali soluble sulfonamide.parts by volume of caustic soda solution of 10 percent strength areadded and the whole is thoroughly agitated. The aqueous layer isextracted again once with 150 parts by volume of benzene, and the twobenzene extracts are washed in succession with 50 parts by volume of acaustic soda solution of 10 percent strength and 50 parts by volume ofwater. By evaporating the dried benzene solution, there are obtainedparts of the solvent-free benzcnc sulfonic acid ester of pentaethyleneglycol monomethyl ether in the form of a colorless oil.

40 parts of the latter oil are introduced dropwise in the course of onehour, while stirring, at 100 C. into a solution of 2.3 parts of sodiumin parts by volume of dicthylcne glycol, and the reaction mixture ismaintained at C. overnight. After being cooled, it is mixed with 250parts by volume of water and shaken well with 100 parts by volume ofchloroform. Extraction is repeated a further 7 times with 100 parts byvolume of chloroform on each occasion, and the chloroform extracts areseparately washed 4 times with 100 parts by volume of water on eachoccasion. By evaporating the chloroform extracts there are obtained 32parts of an oil residue. from which 29.5 parts of heptaethylene glycolmonomethyl ether distil in the form of a colorless oil under a highvacuum of 0.005 mm. pressure of mercury at C.

5.2 parts of potassium are then dissolved at 100 C. while stirring, inan atmosphere of hydrogen in 95 parts of heptacthylene glycol monomethylether, the solution is cooled to 40 C. and 6 parts of chloroacetic acidare added. By working up in a manner analogous to that described inExample 1 there are obtained, in addition to 70 parts of regeneratedheptaethylene glycol monomethyl ethcr 22.5 parts of the ether ofheptaethylene glycol monomethyl ether with glycollic acid in the form ofa yellow oil which dissolves well in water, ethanol and benzene.

Example 7 The acid chloride (obtained in a manner analogous to thatdescribed in Example 6 from 6 parts of the ether from heptaethyleneglycol monoethyl ether with glycol- ]ic acid) is dissolved in 25 partsby volume of toluene and mixed at 0 C. first with a solution of 6 partsof diphenylamine in 20 parts by volume of toluene, and then with asolution of 1.2 parts of pyridine in 5 parts by volume of toluene. Themixture is allowed to stand for a few hours, then it is taken up in 150parts by volume of chloroform, and the solution is extracted byagitation with 2 N-su1furic acid, a 2 N-solution of caustic soda in theform of a bright yellow oil.

Its turbidity point is 68-69 C. 10 percent strength).

By reacting diphenylamine by the method described above with the acidchloride of the ether of octaethylene glycol monomethyl ether withglycollic acid described in Example 2, there is obtained the ether ofoctaethylene glycol monomethyl ether with glycollicacid-NrN-diphenylamide of the formula CH .(O.CH:.C K940131110 O.N

lts turbidity point is 74 C. (aqueous solution of 10 percent strength).

In a similar manner there can be obtained from the acid chloride of theether of pentaethylene glycol monomethyl ether with glycollic aciddescribed in Example 1, the ether of pentaethylene glycol monomethylether with glycollic acid-N:N-diphenylamide having a turbidity point of55 C. (aqueous solution of 10 percent strength).

(aqueous solution of Example 8 0.7 part of sodium is dissolved at 100 C.in 35 parts of hepta-ethylene-glycol-mono-methyl ether of boiling point150 C. (0.005 mm. Hg) in an atmosphere of hydrogen. While stirringvigorously, 7.5 parts of apoint 150 C. (0.005 mm. Hg) in an atmosphereof amide are then added in portions and heating to 110 C. continued for14 hours.

After cooling, 200 parts by volume of water are added and the mixture isextracted three times with 200 parts by volume of benzene each time. Thebenzene layers are then successively extracted twice with 200 parts byvolume of water, then dried over sodium sulfate and evaporated. Thereare obtained as a residue 16.4 parts of the ether oihepta-ethylene-glycol-mono-methyl ether with glycollicacid-N-butyl-(n)-N 2:6 dimethylphenylamide of the formula This residueis a faintly yellow-colored oil which dissolves readily in ethanol,benzene, ethyl acetate and cold water. For purification, an aqueoussolution of percent strength is treated with a small amount of animalcharcoal, filtered, and the filtrate saturated with sodium chloride andextracted with benzene. On evaporation of the solvent, the new compoundis obtained as a practically colorless oil of turbidity point 62 C. (10%aqueous solution).

The u-chloracetic acid-N-butyl-(n)-N-2:6-dimethylphenylamide can beprepared in the following manner:

A solution of 8.9 parts of N-butyl(n)-2:6'dimethylaniline in 25 parts byvolume of acetone is mixed at 10 C. and while being vigorously stirred,first with a solution of 8 parts of chloracetyl chloride in 10 parts byvolume of acetone and then with parts by volume of a saturated sodiumacetate solution. The mixture is then extracted with 100 parts by volumeof ether and the ethereal solution extracted by agitation three timeswith 50 parts by volume of 2 N-sulfuric acid, three times with 50 partsby volume of saturated sodium bicarbonate solution, and three times with50 parts by volume of water. The ethereal solution is dried over sodiumsulfate. On evaporation, 8 parts of a-chloracetic acid-N-butyl-(n)-N-2:6-dimethyl-phenyl-amide are obtained as a viscous oil whichsolidifies after a short while. This new compound boils at 102l03 C.(0.01 mm. Hg), can be recrystallized from petroleum ether, and thenmelts at 40-41 C.

The ether of hepta-ethylene-glycolmono-methyl ether with glycollicacidN-butyl-(n)-N-2:6-dimethylphenylamide can also be prepared by aprocess analogous to that described in Example 1.

By reacting in the manner described in this example achloracetic acid Nbutyl (n) N-2z6-dirnethylphenylamide with the sodium compound ofhexa-ethyleneglycol-mono-methyl-ether, there is also obtained a goodyield of the ether of hexa-ethylene-glycolmono-methyl ether withglycollic acid-N-butyl-(n)-N-2:6-dimethylphenyl-amide of the formulawhose turbidity point is at 55 C. (10% aqueous solution).

By an analogous reaction of the a-chloracetic acid-N-butyl-(n)-N-2:6-dimethylphenyl-amide with the sodium compound oftetra-ethyleneglycol-mono-rnethyl ether there is obtained the ether oftetra-ethyleneglycol-monomethyl ether with glycollicacid-N-butyl-(n)-2:6-dimethylphenyl-amide of the formula which is acolorless oil boiling at 183-184 C. (0.01 mm. Hg) and has a turbiditypoint of 39 C. (10% aqueous solution).

When the u-chloracetic acidN-hexyl-(n)-2:6-dimethyl-phenyl-amide isreacted with the sodium compound ofhexa-ethylene-glycol-monomethyl-elher in the manner described in thisexample, there is also obtained a very good yield of the ether ofhexa-ethylene-glycolmonomethyl-ether with glycollicacid-N-hexyl-(n)-N-2:6- dimethyl-phenyl-amide of the formula Itsturbidity point is 46 C. (aqueous solution of 10 percent strength). Thewchloracetic acid-N-hexyl-(n)- 2:G-dimethyl-phenyl-amide used here isprepared in a manner analogous to a-chloracetic acid-N-butyl-(n)-2:6-dimethyl-phenyl-amide and boils as a colorless oil at 123 C. under 0.04mm. of pressure.

By an analogous reaction of the a-chloracetic acid-N-heptyl(n)-N-2:fi-dirnethyl-phenyl-amide with the sodiurn compound ofhexa-ethylene-glycol-monomethyl ether there is obtained the ether ofhexa-ethylene-glycol- 1 1 monomethyl ether with glycollicacid-N-heptyl-(n)-2:6- dimethyl-phenyl-amide of the formula Itsturbidity point is 46 C. (aqueous solution of per cent strength). Thea-chloracetic acid-N-hcptyl-(n)-2:6 dimethyl-phenyl amide used heredistils as a colorless oil at 127 C. under 0.008 mm. of pressure.

Example 9 1.1 parts of sodium are dissolved at 90400 C. in parts ofdi-ethylene glycol while stirring vigorously. Also while stirringvigorously, a solution of 12 parts of w chloracetic acid N butyl(n)-N-2:6-dimethyl-phenylamide in 10 parts by volume ofdi-ethyleneglycol is run in at C. and the temperature is then maintainedat C. for IS hours. After cooling, 200 parts by volume of water areadded and the mixture extracted three times with 200 parts by volume ofbenzene. The benzene solutions are extracted separately and insuccession twice with 200 parts by volume of water, dried over sodiumsulfate, and evaporated. The residue is distilled at 165 C. (0.01 mm.Hg). In this manner, 13.2 parts of the ether of di-ethyleneglycol withglycollic acid-N-butyl- (n)-N-2:6-dimethyl-phenyl-amide of the formula lcan l are obtained. it is a colorless oil which readily dissolves inethanol, benzene, ethyl acetate and cold water and has a turbidity pointof 28 C. (10% aqueous solution).

By analogous reaction of the wchloracetic acidN-butyl-(n)-N-2zo-dimethylphenyl-amide with the monosodium compound oftri-ethyleneglycol there is obtained a good yield of the ether oftri-ethyleneglycol with glycollicacid-N-butyl-(n)-N-2:6-dimethylphenyl-amide of the formula (Ell;

It is a colorless oil which boils at 178 C. (0.01 mm. Hg), and has aturbidity point of 48 C. (10% aqueous solution).

Example 10 The acid chloride described in Example 1 and obtained from 78parts of the ether of pentaethylene glycol monomethyl ether withglycollic acid is dissolved in 200 parts by volume of toluene. Asolution of 59 parts of hydrochloride of 2:6dimethyl-4-(n)-butoxy-aniline, 40 parts of pyridine and 300 parts byvolume of toluene is added dropwise at 0 C. while stirring. Afterallowing the mixture to stand for 3 hours at room temperature, it isdiluted with 500 parts by volume of toluene and extracted by agitationthree times with 300 parts by volume of 2 N-sulfuric acid, twice with300 parts by volume of l N-solution of caustic soda and once with 300parts by volume of water. The aqueous layers are extracted consecutivelytwice with 500 parts by volume of toluene. The combined toluene layersare then concentrated and from these there are obtained as residue afterdegasification in high vacuum 110 parts of the ether of pentaethyleneglycol 12 monomethyl ether of glycollic acid-N-Z:6-dimethyl-4-(n)butoxyphenyl amide of the formula (EYE;

This product is a pale yellow oil which dissolves well in ethanol,benzene, ethyl acetate, ether and cold Water. For the purpose ofpurification the substance can be dis tributcd between water and etherin a ratio of 10 to 1 and extracted from the water with chloroform, analmost colorless oil being obtained.

The product has a turbidity point of 44 ous solution of 10 percentstrength).

The hydrochloride of 2:6-dimethyl-4-(n)-butoXy-aniline used as startingmaterial may be prepared as follows:

126 parts of 2z6-dimethyl-4-hydroxy-azo-benzene are dissolved in asolution of parts by volume of 4 N- sodium methylate in methanol and 500parts by volume of methanol and mixed with 61.5 parts by volume of N-butylbrornide. The whole is boiled under reflux for 15 hours and thenpoured slowly into a well stirred mixture of 2000 parts of ice, 4000parts by volume of water and 230 parts by volume of 2 N-caustic sodasolution. The red precipitate is filtered off and washed with wateruntil neutral. After drying, the product is recrystallized from 800parts by volume of methanol (cooling to l5 C.), 88 parts of pure2:6-dimethyl-4--butoxy-azobenzene being obtained in the form of redneedles melting at 47-48 C.

From this compound there is obtained on hydrogenating with half thequantity of Raney-nickel in 12 times the quantity of ethanol, a mixtureof aniline and 2z6-dimethyl-4-butoxy-aniline, which, after filtering offthe catalyst and distilling off the solvent, is separated bydistillation in vacuo. The 2:6-di1ncthyl-4-butoxy-aniline boils at156-157" C. under 11 mm. pressure of mercury and can be dissolved hot infour times the quantity of hydrochloric acid of 10 percent strength.From this solution the hydrochloride can be crystallized out on coolingin the form of colorless flakes. For the purpose of purification theproduct may be recrystallized from methanolic hydrochloric acid or from2 N-hydrochloric acid with the addition of active charcoal. The purehydrochloride melts with decomposition at 190492" C.

In the same way the ether of hexaelhylene glycol monomethyl ether withglycolic acid-N-2:6-dimethyl-4-(n)- butoXy-phenyl amide of the formulaC. aquecan be prepared from the acid chloride of the ether ofhexaethylene glycol monomethyl ether of glycollic acid.

The product has a turbidity point of 5l C. (aqueous solution of 10percent strength).

The glycollic acid used here may be prepared as follows:

2.3 parts of sodium are dissolved hydrogen atmosphere in 60 whilestirring in a parts of hexaethylene glycol monomethyl ether heated to90-95 C. The solution is then cooled to 30 C. and 12.8 parts of thesodium salt of chloracetic acid added while stirring vigorously.Stirring is continued for 2 hours at 80 C. and the whole is then allowedto stand for 12 hours. E00 parts by volume of water and 5 parts byvolume of 2 N-caustic soda solution are then added to the mixture. Inorder to remove the excess of heaxethylene glycol monomethyl ether, thealkaline solution is extracted once with 300 parts by volume ofchloroform and five times with parts by volume of chloroform. Thechloroform layers are first washed consecutively twice with 50 parts byvolume of water, then combined and concentrated. The residue consists of30 parts of regenerated hexaethylene glycol monomethyl ether.

The combined aqueous, alkaline layers are acidified with 15 parts byvolume of concentrated hydrochloric acid and then extracted once with300 parts by volume of chloroform and five times with 150 parts byvolume of chloroform. From the chloroform solution there are obtainedafter concentration and degasification in high vacuum 33 parts of theether of hexaethylene glycol monomethyl ether with glycollic acid as ayellow oil. The crude ether-acid can also be purified by way of itsmethyl ester. The latter is prepared by dissolving the acid in 100 partsby volume of ether and reacting it with an ethereal solution ofdiazomethane. The methyl ester distils as a colorless oil at l48150 C.under 0.01 mm. pressure and can easily be converted back by alkalinehydrolysis into the polyether carboxylic acid which in the pure state isa practically colorless oil soluble in water, ethanol and benzene.

Example 11 The ether of pentaethylene glycol monomethyl ether withglycollic acid N bntyl-(n) -N-2:6-dimethylphenyl amide obtained inExample 1 may also be prepared as follows:

1.4 parts of sodium are dissolved at 90-100" C. in 40 parts of ethyleneglycol while stirring vigorously. 15.4 parts of a-chloraceticacid-N-butyl-(n)-N-2:6-dimethylphenyl amide are added at 100 C. whilestirring vigorously and the whole is allowed to stand for 15 hours at110 C. After cooling, 200 parts by volume of water are added, and theproduct is extracted twice with 200 parts by volume of benzene. Thebenzene solutions are extracted by agitation twice consecutively with200 parts by volume of water, dried over sodium sulfate and evaporated.The residue is distilled at 138 C. under 0.01 mm. pressure. In thismanner there are obtained 14.7 parts of the ether of ethylene glycolwith glycollic acid-N-butyln) -N-2 6-dimethylphenyl amide of the formulaThis amide is dissolved in 60 parts by volume of benzene and, whilestirring thoroughly, 13 parts of benzene sul fochloride and 4.2 parts ofpulverized sodium hydroxide are added simultaneously so that thetemperature remains between 3040 C. and the reaction mixture remainsalkaline. Stirring is continued for an hour at room temperature and thewhole is then allowed to stand for 15 hours. 70 parts by volume of waterand 50 parts by volume of benzene are then added while stirring. The twolayers are separated and the aqueous solution is extracted with 50 partsby volume of benzene. The combined benzene layers are agitated for threehours with parts by volume of ammonia of percent strength, thenextracted rapidly with 50 parts by volume of 2 N-caustic soda solutionand 50 parts by volume of water, dried over sodium sulfate andevaporated. There are thus obtained 21 parts of benzene sulfonic acidester of the ether of ethylene glycol with glycollic acid- N-butyl-(n -26-dimethylphenyl amide.

A solution of this sulfonic acid ester in 10 parts by volume oftetraethylene glycol monomethyl ether are added dropwise at 100 C. whilestirring well to a solution of 1.2 parts of sodium in 40 parts by volumeof tetraethylene glycol monomethyl ether and the mixture is heated for15 hours at 1l0-120 C.

After cooling, 300 parts by volume of water are added and the product isextracted three times with 300 parts by volume of benzene. The benzenelayers are extracted by agitation in succession twice with 300 parts byvolume of water, then dried over sodium sulfate and evaporated. Asresidue there are obtained 19 parts of the ether of pentaethylene gylcolmonomethly ether of glycollic acid-Nbutyl-(n)-N-2:6-dirnethylphenylamide in the form of a viscous oil which has a turbidity point of 50 C.(aqueous solution of 10 percent strength). The oil can be purified bydistillation in high vacuum. (Boiling point 178-180 C. under 0.007 mm.pressure.)

Example 12 5.9 parts of the ether of 1:2-propylene-glycol with glycollicacid-N-butyl- (n -N-2: fi-dimethyl-phenyl-amide of the formula H: areheated with agitation with 7 parts by volume of ethylene oxide and 0.02part of pulverized sodium hydroxide in a bomb tube for 15 hours at 170C.

The contents of the bomb tube are then dissolved in parts by volume ofwater, treated with 2 parts of animal charcoal and then extracted byagitation with 50 parts by volume of petroleum ether (boiling point 4065C.) to separate ofi any constituents which are difficultly soluble inwater. After evaporating the petroleum ether layer, 0.27 part of awater-insoluble oil is obtained. The aqueous layer is extracted threetimes with 50 parts by volume of benzene, the benzene layers areevaporated and there are obtained 8.7 parts of a faintly yellow oilconsisting of a mixture of ethers of poly-ethylene-glycol with the etherof 1:2-propylene glycol with glycollic acid-N-butyl-(n)-N-2:6-dimethylphenyl-amide of the formula.

CH; 1H9

The separation of this mixture into various fractions can be effected bydistribution between two liquid phases, possibly according to theprinciple of countercurrent extraction.

For example it is possible to proceed in the following manner:

8.7 parts of the oil obtained above are dissolved in 100 parts by volumeof water and extracted three times with 50 parts by volume of ether. Thefirst ether layer yields on evaporation an oily fraction of 1 parthaving a turbidity point of 26 C. (aqueous solution of 10 percentstrength). From the second ether layer there is obtained a fraction of0.8 part with a turbidity point of 41 C. and from the third ether layera fraction of 0.3 part with a turbidity point of 50 C.

In order to avoid an emulsion, 5 parts of sodium chloride are dissolvedin the aqueous layer and extraction is carried out first with a mixtureof 25 parts by volume of ether with 25 parts by volume of benzene andthen with 50 parts by volume of benzene. The ether and benzene layeryields a fraction of 6 parts having a turbidity point of 71 C. and thebenzene layer a fraction of 0.55 part with a turbidity point of 87 C.

The ether of 1:2-propylene-glycol with glycollic acid-Nbutyl-(n)-2:6-dimethyl-phenyl-amide used as starting material isprepared in an analogous manner to that of the ether of ethylene glycolwith glycollic acid-N-butyl- (n)-N-2:6-dimethyl-phenyl-amide describedin Example 11 by using 1:2-propylene glycol instead of ethylene glycol.

The new compound is a colorless water-insoluble oil which dissolves wellin ordinary organic solvents and distils at 132 C. under 0.01 mm. ofpressure.

Example 13 0.3 part of sodium is dissolved at 90-95 C. while stirring inan atmosphere of hydrogen in 23 parts of octa ethylyene glycol w methylether w [2 hydroxy-3-ethoxy-propyl-ether-(1)]. 3.8 parts ofe-chloracetic acid-N-heptyl-(n)-2:6-dimethyl-phenyl-amide are then addedwhile stirring vigorously and the whole is heated for 15 hours at 110 C.

After cooling, 150 parts by volume of water are added and the solutionis extracted three times with 150 parts by volume of benzene. Thebenzene layers are extracted by agitation twice consecutively with 150parts by volume of water. then dried over sodium sulfate and evaporated.As residue there are obtained 8.4 parts of the ether of octa-ethyleneglycol-w-methyl ether-d-[Z-hydroxy-3-ethoxy-propyl ether-( 1)] withglycollic acid-N- heptyl (n) N 2:6 dimethyl phenyl amide of the formulaCH 07H] I a a (1:113 OCnHg This product is a faintly yellow oil whichdissolves well in ethanol, ether, benzene, ethyl acetate and cold water.Slight impurifications can be removed by extraction by agitation with alittle ether of an aqueous solution of l percent strength. The puresubstance has a turbidity point of 51 C. (aqueous solution of percentstrength).

The u-chloracetic acid-N-heptyl-(n)-N-2:6-dimethylphenyl amide used asstarting material is prepared in a manner analogous to thea-chloracetic-acid-N-butyl-(n) N-Zzfi-dimethyl-phenyl amide described inExample 8 and boils as a colorless oil at 127 C. under 0.008 mm. ofpressure.

The octa-c1hylene-glycol-wmethyl ether-w'-[2-hydroxy- 3-ethoxy-propylether-(1)] used as starting material in this example can be prepared asfollows:

2.4 parts of sodium are dissolved at 100 C. While stirring in 41 partsof glycerine-w-cthyl ether, having a boiling point of 118420 C. under 10mm. of pressure, in a flask fitted with stirring means and withexclusion of moisture. Then in the course of 4 hours 52.4 parts of thebenzene sulfonic acid ester of octa-ethyleneglycolmonomethyl ether,prepared by reacting benzene sulfonic acid ester ofpenta-cthyleneglycol-rnonomethyl ether with tri-ethylene-glycol andreacting the resulting octaethylene-glycol-monomethyl ether of boilingpoint 165 C. under 0.005 mm. of pressure with benzene sulfonic acidchloride in a manner analogous to that described in Example 1. are addeddropwise at a temperature of 95-l05 C. while stirring. After heating to100-110 C. the mixture is cooled overnight and rinsed with 100 parts byvolume of chloroform and 50 parts by volume of water in a separatingfunnel. In a second and third separating funnel l2.5 parts by volume ofwater are prepared. The chloroform layer is drained off after shakingfrom the first into the second and then into the third separatingfunnel. The three aqueous layers are extracted by agitation three timesmore with 100 parts by volume of chloroform on each occasion. Thecombined chloroform solutions dried with sodium sulfate are evaporated;after drying at 100 C. under 10 mm. of pressure, there are obtained 49.9parts of a light brown oily residue. When distilled in high vacuum thechief part passes over at l95-2l5 C. under 0.01 mm. of pressure, fromwhich there are obtained on distillation 34 parts of octa ethyleneglycol w methylether whydroxy 3 ethoxy propyl ether (1)] boiling at207-2ll C. under 0.01 mm. of pressure in the form of a colorless,water-soluble oil.

Example 14 0.35 part of sodium is dissolved at C. while stirring in anatmosphere of hydrogen in 30 parts of hexaethylene-glycol-monomethylether. 4 parts of a-chloracetic acid-N:N di-ortho-tolyl amide are addedat C. while stirring vigorously and the mixture is heated for 3 hours at140 C and for 12 hours at 110 C. After cooling, parts by volume of waterare added and the solution is extracted three times with 150 parts byvolume of benzene. The benzene layers are extracted by agitation twicein succession with 150 parts by volume of water, then dried over sodiumsulfate and evaporated. As residue there are obtained 7.4 parts of ayellow oil. To the latter are added 70 parts by volume of Water and theweakly turbid aqueous solution is extracted by agitation for the purposeof removing insoluble constituents and small quantities of by-productsfirst with 50 parts by volume of petroleum ether and then with 30 partsby volume of ether.

The aqueous clear solution is then extracted twice with 50 parts byvolume of benzene. The benzene layers are extracted with 30 parts byvolume of water, dried over sodium sulfate and evaporated. As residuethere are obtained 6.1 parts of the ether ofhexa-ethylene-glycol-monomethyl ether with glycollicacid-NzN-di-orthotolyl amide of the formula The product is a faintlyyellow oil which dissolves well in ethanol, benzene, ethyl acetate andcold water and has a turbidity point of 52 C. (aqueous solution of 10percent strength).

The a-chloracetic acid-NzN-di-ortho-tolyl amide used as startingmaterial in this example is prepared as follows:

A solution of 4 parts of ortho-ditolyl-amine and 3-4 parts ofchloracetyl chloride in 40 parts by volume of toluene is boiled underreflux for 5 hours, evaporated in vacuo and the solid residue is twicecrystallized from a mixture of ethyl acetate and petroleum ether. Inthis manner there are obtained 4.8 parts of a-chloracetic acid-N:N-di-ortho-tolyl amide as white crystals of melting point l23-124 C.

What is claimed is:

l. Poly-1:2-glycol ethers of the formula wherein R stands for a loweralkyl radical and n represents a whole number from 4 to 8 inclusive. 2.Poly-1:2-glycol ethers of the formula wherein n represents a wholenumber from 4 to 8 inelusive.

3. The poly-1:2-glycol ether of the formula 18 taining at most 7 carbonatoms, and Z represents a memoer selected from the group consisting of2,6dimethylphenyl and 2,6-dimethyl-4-lower-alkoxyphenyl radicals.

4. Poly-1:2-glycol ethers of the formula:

R-(OCHIOHflr-O-Olh-OOIIIZ wherein n represents a whole number from 2 to20 in- 5 elusive, R represents a member selected from the groupconsisting of hydrogen and alkyl radicals containing at most 7 carbonatoms, Y represents a member of the group consisting of hydrogen and analkyl radical con- References Cited in the file of this patent UNITEDSTATES PATENTS 2,520,551 Kilgore Aug. 29, 1950

4. POLY-1:2-GLYCOL ETHERS OF THE FORMULA: